We have developed enough evidence for a functional interaction between chemokines, particularly the HIV co-receptors, and the opioid system in the brain. Indeed, recently we have shown that although morphine currently represents the best option for treating acute and chronic severe pain, elevated brain levels of Stromal cell-Derived growth Factor-1alpha (SDF-1 alpha/CXCL12), the ligand of the HIV co-receptor CXCR4 (a condition that occurs with neuroinflammatory diseases, including HIV encephalitis), diminish the analgesic effect of morphine (Adler et al., 2006). Our present preliminary data show that this effect is not a general characteristic of all opioid medications. The administration of SDF-1 alpha/CXCL12 into the brain fails to alter the antinociceptive action of buprenorphine, while it reduces methadone-induced antinociception. Buprenorphine was approved by the FDA in 2002 for use in supervised withdrawal and maintenance treatment of opioid dependence. Compared to methadone, the most common clinically used opioid medication for pain and opioid dependence management, buprenorphine is a partial mu-opioid agonist, a powerful analgesic in both rodents and humans, has a very long-lasting efficacy, high safety profile, low level of physical dependence and has not been shown to produce adverse drug interaction with antiretroviral therapy. While as yet unexplored, the unique pharmacological characteristics of this opioid together with its lack of interaction with the HIV co-receptor (CXCR4) may make it more suitable and effective for treating pain (acute and chronic) and/or opioid dependence under HIV infection conditions compared to methadone. The HIV-1 envelope glycoprotein (gp120) has been detected in the brains of HIV-1-infected individuals. It is known to elicit inflammation in the brain through binding and activating CXCR4. The central goal of this proposal is to test whether the presence of gp120 in the brain modulates the analgesia and the development of tolerance and dependence to buprenorphine and methadone. Based on the fact that the administration of the SDF-1 alpha/CXCL12 into the brain diminishes methadone-induced analgesia, while it fails to interfere with buprenorphine, and that SDF-1 alpha/CXCL12 and gp120 both bind to CXCR4, it is a tenable hypothesis that buprenorphine functions more effectively in the presence of gp120 in the brain, as compared to methadone, via a mechanism that is independent of the CXCR4 receptor. In this proposal, we will investigate the in vivo consequences of the central administration the gp120 on analgesia (AIM # 1) and the development of analgesic tolerance and dependence in response to chronic buprenorphine and methadone (AIM # 2). Whether gp120 interacts with opioid medications via chemokine receptor mechanisms will be investigated. These studies are the first to examine an important issue that until now remains unexplored: the analgesic function, development of tolerance and dependence to the most common clinically used opioids for pain and opioid addiction management (buprenorphine and methadone) in the presence of gp120 in the brain. Knowledge of HIV and buprenorphine/methadone interaction has great implications for pain and/or opioid dependence management with opioid medications in HIV patients. The opportunities for effectively addressing the functional interaction between gp120 and these two opioid medications, is relevant for public health, particularly the field of HIV-related pain and opioid dependence. PUBLIC HEALTH RELEVANCE: These studies are the first to examine an important issue that until now remains unexplored: the analgesic function, development of tolerance and dependence to the most common clinically used opioids for pain and opioid addiction management (buprenorphine and methadone) in the presence of HIV-1 envelope glycoprotein (gp120) in the brain. The proposed studies, if successful will reveal for the first time, which of the most common clinically used opioid medications for pain and opioid dependence management (buprenorphine or methadone) is more effective and safe when it is used acutely and chronically under neuroinflammation produced by HIV-1 envelope glycoprotein (gp120). Knowledge of HIV and buprenorphine/methadone interaction has great implications for pain and/or opioid dependence management with the opioid medications in HIV patients. The opportunities for effectively addressing the functional interaction between gp120 and these two opioid medications, is relevant for public health, particularly the field of HIV-related pain and opioid dependence.